Impaired glucose tolerance (IGT) is common in the U.S. population. The prevalence of impaired glucose tolerance increases from 11% in the general population aged 20-74 years to 24% in those 40-75 years of age with a family history of diabetes and a body weight greater than 120% of normal. Subjects with impaired glucose tolerance are at high risk for the development of cardiovascular disease as well as non-insulin dependent diabetes mellitus (NIDDM), also known as Type 2 diabetes.
Impaired glucose tolerance is characterized by early subtle defects in pancreatic β-cell function, accompanied by insulin resistance. These early defects include an impaired ability of the β-cell to sense and respond to small changes in plasma glucose concentrations with appropriate levels of insulin secretion, and a mild shift to the right of the glucose insulin secretion dose-response curve. The glucose sensing and fast insulin secretion response abilities of the β-cell are lost very early in the course of IGT when 2-hour glucose levels are minimally elevated. The deterioration of glucose control in IGT with time is predominantly due to progressive impairment of β-cell function. This leads, in many cases, to deteriorating conditions of hyperinsulinemia, obesity, and cardiovascular disease, sometimes known as Syndrome X. In many cases advanced IGT conditions lead to definitive loss of glucose control and the deleterious onset of NIDDM.
As indicated, the condition of IGT carries serious health risks. The IGT patient is often obese and has high plasma levels of insulin, which are often toxic. These high insulin levels result generally from the continually increased inability of muscle, other tissue and fat cells to utilize insulin to effect the uptake of glucose from blood plasma. The IGT condition gives rise to increased risks for a whole range of cardiovascular diseases.
Glucagon-like peptide-1 (GLP-1), a natural enteric peptide, is secreted from the L-cells of the gut, and acts as an incretin hormone stimulating pancreatic β-cells to secrete insulin in a glucose dependent manner. Its therapeutic potential in NIDDM has been previously demonstrated, in that exogenous infusion of pharmacological doses of GLP-1 generally reduced plasma glucose levels. However, GLP-1 did not significantly improve β-cell function in NIDDM. Nathan DM, Schreiber E, Fogel H, Mojsov S, Habener J F. Insulinotropic action of glucagon-like peptide-1 (7-37) in diabetic and nondiabetic subjects. Diabetes Care 15:270-276, 1992; Gutniak M, Ørskov C, Holst J J, Ahrén B, Efendric S. Antidiabetogenic effects of glucagon-like peptide-1 (7-36) amide in normal subjects and patients with diabetes mellitus. N Engl J Med 326:1316-1322, 1992; Nauck M A, Kleine N. Orskov C, Holst J J, Willms B, Creutzfeldt W. Normalization of fasting hyperglycemia by exogenous glucagon-like peptide-1 (7-36 amide) in type II (non-insulin-dependent) diabetic patients. Diabetologia 36:741-744, 1993; Gutniak M K, Linde B, Holst J J, Efendie S. Subcutaneous injection of the incretin hormone glucagon-like peptide-1 abolishes postprandial glycemia NIDDM. Diabetes Care 17:1039-1044, 1994; Rachman J, Gribble F M, Barrow B A, Levy J C, Buchanan K D, Turner R C. Normalization of insulin responses to glucose by overnight infusion of glucagon-like peptide 1 (7-36) amide in patients with NIDDM. Diabetes 45:1524-1530, 1996; Rachman J, Barrow B A, Levy J C, Turner R C. Near-normalization of diurnal glucose concentrations by continuous administration of glucagon-like peptide-1 (GLP-1) in subjects with NIDDM, Diabetologia 40:205-211, 1997.
The IGT condition is not currently treatable. It is, however, a recognizable disease condition associated with serious health risks. In general, the IGT condition progressively deteriorates in terms of its symptoms and often leads to loss of plasma glucose control which constitutes type 2 diabetes. There is a need for a therapy.
Numerous studies over the past several years have demonstrated that the application of GLP-1 in cases of NIDDM lowers glucose and insulin levels in the blood, and hence should be a promising therapy for that disease. However, no studies to date have shown that GLP-1 has a potential to correct the loss of the ability of β-cells to sense and quickly respond with the secretion of insulin when blood glucose increases. It is this deterioration in the ability to respond and to closely link the sensing of increases in blood glucose to insulin secretion from the β-cells which is the principal cause of the IGT condition. In previous studies the application of GLP-1 to NIDDM subjects demonstrated an ability to normalize fasting plasma glucose and to stimulate cumulative β-cell insulin secretion. However, GLP-1 infused overnight in NIDDM subjects did not improve glucose responses to meals the next day. When GLP-1 was infused for 19 hours, overnight and during three standard meals in subjects with NIDDM, plasma glucose levels were reduced, but the impaired post-prandial β-cell function was only slightly improved.
β-cell responses to prolonged infusion of GLP-1 have not been previously studied in subjects with IGT and, while there has been no indication that the result would be different than with GLP-1 infusions in NIDDMs, detailed studies of the effect of GLP-1 on β-cell responses to small increases and decreases in plasma glucose concentrations have not been heretofore performed.
Accordingly, a method to arrest the progression of IGT and restore normal glucose metabolism conditions is needed.
It is therefore an object of the present invention to provide a method of restoring or improving β-cell function and sensitivity, and thus insulin secretion patterns, in response to plasma glucose levels in a host having impaired glucose tolerance.
A further object of the invention is to provide a method to delay or prevent the deterioration of β-cell function which is responsible for the progression of impaired glucose tolerance into the loss of control over plasma glucose which characterizes the onset of NIDDM.
A yet further object of the invention is to ameliorate cardiovascular disease effects of IGT, thereby decreasing cardiovascular and stroke risks.
The method of accomplishing these and other objects will be apparent from the following detailed description.